Use of sustained release antibiotic compositions in ophthalmic surgical procedures

ABSTRACT

An improved method of sterilizing the field of surgery prior to an ophthalmic surgical procedure is described. The invention eliminates the need for painful and potentially traumatic injections of antibiotics by utilizing sustained release compositions which allow the antibiotics contained therein to penetrate deeply into the eye, thereby ensuring a sterile field of surgery during intraocular surgical procedures. The compositions may also be utilized to prevent post-surgical infections.

BACKGROUND OF THE INVENTION

The present invention relates to sustained release pharmaceuticalcompositions containing one or more antibiotics. The invention is alsodirected to the use of such compositions to sterilize the tissues in thearea of surgery (i.e., the "surgical field" or "field of surgery") priorto a surgical procedure and to prevent post-surgical infections.

Ophthalmic surgical procedures currently involve the topical applicationof betadine solution to the eyelid and other tissues adjacent to the eyeprior to surgery. The preoperative procedures may also include topicalinstillation of argyrol to facilitate removal of mucus and other debrispresent on the cornea and conjunctiva. However, the foregoing proceduresdo not result in sterilization of the ophthalmic tissues which form thesite of the surgery (e.g., the cornea, sclera or various otherophthalmic tissues).

Antimicrobial agents such as the aminoglycosides, penicillins andcephalosporins, being relatively insoluble in lipids, penetrate the eyepoorly after systemic administration. Therefore, the surgical field iscurrently sterilized by subconjunctival injection of any one of variousantibiotics. The most commonly used drug in subconjunctival injection isgentamicin (about 30 mg per injection). This method involves theinsertion of a 20-gauge needle into the subconjunctival space, takingcare not to pierce the conjunctiva; 0.1 ml to 1.0 ml of antibiotic isinjected. This technique permits significant antibiotic to enter thecorneoscleral limbus near the subconjunctival injection site. However,such injections present a significant risk of injury to ophthalmictissues of performed improperly. Even when proper procedures arefollowed, such injections are painful and inherently involve at leastsome undesirable trauma due to the passing of the hypodermic needlethrough very delicate. ophthalmic tissues. In addition, subconjunctivalinjections of antibiotics can result in nonuniform concentrations of theantibiotics in the cornea, and the concentrations attained may beinadequate. For example, the maximum gentamicin concentration attainedin the aqueous humor of rabbits from subconjunctival injection is 8.8ug/g. Although a concentration of 8.8 ug/g would be effective againstsome bacteria, a significantly higher concentration is required for moreresistant strains. Still another problem is the fairly recentdevelopment of bacterial resistance to aminoglycoside antibiotics.

The intravenous ("IV") and oral dosage of quinolones have been suggestedfor prophylactic usage and as an alternative to subconjunctivalinjections. However, the maximum aqueous humor concentration from IVinjection (200 mg) and oral dosage (1 g) of ciprofloxacin in humans is0.16 ug/ml and 0.33 ug/ml, respectively, at one hour afteradministration. This is less than its MIC90 (0.5 ug/g). These non-oculardelivery routes are also associated with higher risks of systemic sideeffects. The topical application of existing antibiotic formulations isuseful in cases of superficial infections, but is inadequate for thedelivery of high concentrations of antibiotics to deeper eye tissuesprior to surgery.

This risk of infection subsequent to ophthalmic surgery is a significantconcern. The post-surgical application of an antibiotic is thereforenormally desirable. However, as with the current procedures forsterilizing the ophthalmic field prior to surgery, the post-surgicaladministration of antibiotics by means of hypodermic injections hassignificant drawbacks.

Accordingly, improved methods of sterilizing ophthalmic tissues prior tosurgery and preventing post surgical infections are needed.

SUMMARY OF THE INVENTION

The present invention is directed to the use of sustained releaseantibiotic compositions to sterilize the field of surgery prior toophthalmic surgical procedures and prophylactically treat post-surgicalinfections. The invention has significant advantages relative to priormethods of sterilizing the field of surgery and prophylacticallytreating post-surgical infections. The principal advantages are asfollows: (1) the drug is more evenly distributed; (2) a MIC is achievedfairly rapidly; (3) the drug has a longer residence time in the corneaand other ophthalmic tissues; and (4) the pain, trauma and inherenthazards of hypodermic injections are avoided.

The compositions of the present invention comprise one or moreantibiotics in a sustained-release vehicle. The preferred antibioticsare quinolones (e.g., ciprofloxacin). The preferred vehicle is a viscousgel. Other types of vehicles which provide for a sustained release ofthe antibiotics, such as a solid insert which is placed in thecul-de-sac of the eye and then gradually erodes as it is bathed withocular fluids, may also be used.

It has been found that the compositions of the present invention enablepotent, ophthalmically acceptable antibiotics to penetrate the anteriorchamber of the eye in concentrations that are bactericidal relative tomost gram-negative and gram-positive organisms. The sustained-release ofantibiotics from the compositions of the present invention enables thetherapeutic objectives of sterilizing the surgical field and preventingpost-surgical infections to be accomplished by means of a singleapplication of the compositions topically to the eye.

DESCRIPTION OF PREFERRED EMBODIMENTS

The antibiotics which may be used in the present invention include allantibiotics which: (1) have potent, broad activity against ophthalmicpathogens; (2) are at least partially water soluble; (3) are capable ofpenetrating the corneal epithelium; and (4) are nontoxic to ophthalmictissues. Antibiotics which satisfy the foregoing criteria are referredto herein as being a "potent, ophthalmically acceptable antibiotic". Thepotent, ophthalmically acceptable antibiotics utilized in the presentinvention preferably have a minimum inhibitory concentration ("MIC")against common ophthalmic pathogens of four micrograms per milliliter (4mcg/ml), or less. Also, the minimum bactericidal concentration ("MBC")of these antibiotics, relative to specified ophthalmic pathogens, ispreferably no more than two times greater than the minimum inhibitoryconcentration thereof.

The most preferred antibiotics are quinolones. Aminoglycosides are alsopreferred. Both of these classes of antibiotics are well known.Representative examples of antibiotics from each of these classes arepresented below:

    ______________________________________                                        Quinolones         Aminoglycosides                                            ______________________________________                                        Ciprofloxacin      Gentamicin                                                 Ofloxacin          Tobramycin                                                 Norfloxacin                                                                   ______________________________________                                    

Other classes of antibiotics which may be utilized includecephalosporins and penicillins. Further examples of antibiotics whichmay be used are listed below:

    ______________________________________                                        Amikacin  Cephalothin        Methicillin                                      Ampicillin                                                                              Chloramphenicol    Oxacillin                                        Carbenicillin                                                                           Clindamycin        Penicillin GK                                    Cefazolin Colistin           Piperacillin                                     Cefoxitin Erythromycin Lactobionate                                                                        Streptomycin                                     Ceftazidime                                                                             Imipenem           Ticarcillin                                      Cefotaxime                                                                              Kanamycin          Vancomycin                                       ______________________________________                                    

The concentration of antibiotic utilized in the compositions of thepresent invention will vary depending on the intended use of thecompositions (i.e., sterilization of the surgical field or prevention ofpost-surgical infections), and the relative antimicrobial activity ofthe specific antibiotic selected. The antimicrobial activity ofantibiotics is generally expressed as the minimum concentration requiredto inhibit the growth of a specified pathogen. This concentration isalso referred to as the "minimum inhibitory concentration" or "MIC". Theterm "MIC90" refers to the minimum concentration of antibiotic requiredto inhibit the growth of ninety percent (90%) of a population ofmultiple strains of a microorganism. The concentration of an antibioticrequired to totally kill a specified population of bacteria or otherpathogens is referred to as the "minimum bactericidal concentration" or"MBC".

The minimum inhibitory concentrations of some of the preferredantibiotics of the present invention, relative to a specific strain ofpseudomonas aeruginosa (i.e., Strain 4N3422), are presented in thefollowing table:

    ______________________________________                                        Antibiotic    MIC (μg/mL)                                                  ______________________________________                                        Amikacin      8                                                               Ceftazidime   1                                                               Cefotaxime    32                                                              Cefoxitin     >32                                                             Ciprofloxacin <0.125                                                          Gentamicin    >8                                                              Imipenem      1                                                               Norfloxacin   <0.5                                                            Piperacillin  <8                                                              Tobramycin    >8                                                              Ticarcillin   32                                                              ______________________________________                                    

The activity of antibiotics against pseudomonas aeruginosa isparticularly important in the present invention, because ophthalmicinfections involving pseudomonas aeruginosa represent an extremelyserious condition which may ultimately result in the loss of theaffected eye. The activities of three particularly preferredantibiotics, ciprofloxacin, gentamicin and tobramycin, relative tomultiple strains of pseudomonas aeruginosa and other ophthalmicpathogens are presented in the following table:

    ______________________________________                                        MIC 90 (μg/ml)                                                                      Ciprofloxacin                                                                           Gentamicin                                                                              Tobramycin                                       ______________________________________                                        Staph. aureus                                                                            0.5         12.5      6.3                                          Staph. epidermidis                                                                       0.4         12.5      56.0                                         Hemo. influenzae                                                                         0.015       0.8       13.4                                         Strep. pneumoniae                                                                        2.0         50.0      34.5                                         P. aeruginosa                                                                            0.5         8.0       20.0                                         ______________________________________                                    

The appropriate concentration for specific antibiotic/vehiclecombinations can be readily determined by persons skilled in the fieldof ophthalmic pharmaceuticals. More specifically, an mount of antibioticsufficient to provide a concentration in the aqueous humor and lacrimalfluid equal to or greater than the MIC90 level for the selectedantibiotic, relative to gram-negative and gram-positive organisms, willbe required. Such amount is referred to herein as "an antimicrobialeffective amount". In general, the compositions of the present inventionwill contain one or more antibiotics in a concentration of from about0.03 to about 30.0 percent by weight, based on the total weight of thecompositions ("wt. %").

The above-described antibiotics are contained in ophthalmicpharmaceutical compositions which provide for sustained release of theantibiotic. The degree of sustained release required may vary dependingon the antibiotic selected. However, a residence time of at least fiveto ten minutes, preferably ten minutes or more, will typically berequired. The composition may be in the form of a solid insert whichgradually erodes when placed in the cul-de-sac of the eye, or a viscousgel which slowly dissolves when contacted with the lacrimal fluid.

The viscous gels utilized in the present invention will generally have aviscosity in excess of 1,000 cps in order to ensure an adequateresidence time in the eye. Any synthetic or natural polymer which iscapable of forming a viscous or a solid insert may be utilized. Inaddition to having the physical properties required to form a viscousgel or solid insert, the polymers must also be compatible with tissuesof the eye. The polymers must also be chemically and physicallycompatible with the above-described antibiotics and other components ofthe compositions. Polymers which satisfy the foregoing criteria arereferred to herein as "ophthalmically acceptable viscous polymers".Examples of suitable polymers include:

natural polysaccharides and gums, such as:

alginates

carrageenan

guar

karaya

locust bean

tragacanth

xanthin

Synthetic polymers, such as:

agarose

Carbopol®

carboxymethylcellulose

hydroxyethylcellulose

hydroxypropylcellulose

hydroxypropylmethylcellulose

methylcellulose

polyvinyl alcohol

polyvinyl pyrrolidone

In addition, proteins and synthetic polypeptides that form viscous gelsand are ophthalmically acceptable can be used to provide betterbioavailability. Typically, proteins that can be used include: gelatin,collagen, albumin and casein.

Polymers which have high molecular weights and, most importantly,physical properties which mimic the physical properties of the mucoussecretions found in the eye are referred to herein as being"mucomimetic". A preferred class of mucomimetic polymers are carboxyvinyl polymers having molecular weights in the range of from about50,000 to about 6,000,000. The polymers have carboxylic acid functionalgroups and preferably contain between 2 and 7 carbon atoms perfunctional group. The gels which form during preparation of theophthalmic polymer dispersion have a viscosity between about 1,000 toabout 300,000 centipoise (cps). Suitable carboxy vinyl polymers includethose called Carhomers, e.g., Carbopol® (B. F. Goodrich Co., Cleveland,Ohio). Specifically preferred are Carbopol® 934, 940, 970 and 974. Suchpolymers will typically be employed in an amount between about 0.05 andabout 8.0 wt %, depending on the desired viscosity of the composition.

The solid inserts described in U.S. Pat. No. 4,540,408 (Lloyd) are alsopreferred; the entire contents of the Lloyd '408 patent are herebyincorporated in the present specification by reference. The solidinserts described in the Lloyd '408 patent comprise an elongatedapplicator having a soluble matrix element disposed at one end thereof.The soluble matrix element contains one or more drugs. The applicatoralso includes a soluble membrane which traverses the applicator, so asto separate the soluble matrix element from the rest of the applicator.When the end of the applicator containing the drug matrix element andsoluble membrane is applied to the eye, the soluble membrane rapidlydissolves, thereby releasing the drug matrix element. The drug matrixelement then slowly dissolves in the lacrimal fluid, releasing the druginto the lacrimal fluid as it dissolves.

Other types of solid inserts, such as the water soluble polymericinserts described in U.S. Pat. No. 4,343,787 (Katz), may also beutilized. The entire contents of the Katz '787 patent are herebyincorporated in the present specification by reference.

The compositions of the present invention will preferably also includeone or more agents to enhance the ocular penetration and absorption ofthe antibiotic. The epithelium is the main barrier to drug penetrationof the cornea. It is possible to enhance the penetration of drugsthrough the epithelium by promoting drug partition into the epithelium,thereby enhancing the overall absorption of drugs applied topically tothe eye. For example, the partition coefficient of ciprofloxacin betweenN-Octanol/0.1M phosphate (pH=7.0) is 0.02, which is low. Consequently,this drug has difficulty penetrating the lipophilic epithelial barrier.The use of a penetration enhancer may therefore be required inconnection with certain antibiotics in order to ensure that an amount ofthe antibiotic sufficient to sterilize the surgical field and/or preventpost-surgical infection penetrates the cornea.

The penetration enhancer generally acts to make the cell membranes lessrigid and therefore more amenable to allowing passage of drug moleculesbetween cells. The penetration enhancers preferably exert theirpenetration enhancing effect immediately upon application to the eye andmaintain this effect for a period of approximately five to ten minutes.The penetration enhancers and any metabolites thereof must also benon-toxic to ophthalmic tissues. Penetration enhancers which meet all ofthe foregoing criteria are referred to herein as "rapid acting,ophthalmically acceptable, corneal penetration enhancers". One or morepenetration enhancers will generally be utilized in an amount of fromabout 0.01 to about 20.0 wt. %, preferably from about 0.01 to about 1.0wt. %.

The preferred penetration enhancers are saccharide surfactants, such asdodecylmaltoside ("DDM"), and monoacyl phosphoglycerides, such aslysophosphatidylcholine. The saccharide surfactants and monoacylphosphoglycerides which may be utilized as penetration enhancers in thepresent invention are known compounds. The use of such compounds toenhance the penetration of ophthalmic drugs is described in commonlyassigned U.S. Pat. No. 5,221,696 and U.S. patent application Ser. No.031,000, filed Mar. 12, 1993 (now U.S. Pat. No. 5,369,095),respectively. The entire contents of the above-identified patent andpatent application are hereby incorporated in the present specificationby reference.

The penetration enhancing monoacyl phosphogylcerides used in the presentinvention have the following structure: ##STR1## wherein one of R₁ andR₂ is hydrogen, thiol, hydroxyl, amino, lower alkyl, lower alkoxy (e.g.,methyl, ethyl, methoxy or ethoxy) or alkyl sulfide and the other is anestefified, etherified or amidified hydrophobic group, and R₃ is ahydrophilic group. The preferred hydrophobic groups include saturatedand unsaturated aliphatic hydrocarbon groups which range from 14 to 24carbons in length with zero to 5 double bonds. The aliphatic hydrocarbongroups can be straight or branched chain and may be substituted by oneor more aromatic, cycloaliphatic or hydrophilic (e.g., hydroxyl, thiol,or amino) groups. Examples of suitable hydrophilic groups (R₃) includeO-inositol, choline, O-choline, O-carnitine, O-(CH₂)₃ -choline,O-glycerol and O-lysophosphatidyl-glycerol.

The preferred monoacyl phosphoglycerides are lysophospholipids, such aslysophosphatidylcholine, lysophosphatidylinositol (lysolecithin),lysocardiolipin, lysodesoxylipids, lysophosphorylipids and∝-lyso-r-O-alkyl or O-alkenyl phospholipids such asDL-∝-Lysolecithin-r-O-hexadecyl and DL-∝-Lysolecithin-r-O-alkyl. Themost preferred monoacyl phosphoglyceride is 1-acyllysophosphatidylcholine (C18:0, C18:1, C16:0 or C16:1). The 1-acyllysophosphatidylcholine C18:0 (lysolecithin) which is most preferred hasthe following structural formula: ##STR2##

The penetration enhancing, substituted glycosides used in the presentinvention have the following structure:

    R.sub.1 --Z--(R.sub.2).sub.x

wherein:

R₁ is a hydrophobic group including saturated and unsaturated aliphatichydrocarbon groups which range from 8 to 28 carbons in length with 1 to5 double bonds, and which can be a straight or branched chain and may besubstituted by one or more aromatic, cycloaliphatic or hydrophilic(e.g., hydroxyl, thiol, ester or amino) groups;

R₂ is a group derived from any cyclic or acyclic saccharide containing4-7 carbons and their isomers;

X is an integer from 1-10; and

Z is an oxy (--O--), ##STR3## thio (--S--), or carboxamido ##STR4##where R₂ is covalently bound to such group.

More specifically, R₁ is preferably a straight 8-18 carbon alkyl chainin hemiacetal linkage (glycoside) to the saccharide; and R₂ ispreferably a group derived from any of a variety of isomericsaccharities containing 5 or 6 carbons. The saccharide can be, forexample, an aldehyde-containing saccharide (glucose, mannose, arabinose,galaclose, xylose); a ketone-containing saccharide (fructose, xylulose,sorbose); a saccharide alcohol (sorbitol, inositol, xylitol, mannitol);a saccharide acid (glucuronic acid, neuramic acid, mannuronic acid); adeoxysaccharide (deoxy-ribose, rhamnose); or an aminosaccharide(glucosamine, galactosamine). Higher order saccharides which arecovalently linked in any of a number of ways to form different isomericstructures can also be utilized. For example, disaccharides such asmaltose, cellobiose, sucrose and lactose, and trisaccharides, such asraffinose, can be utilized.

The preferred penetration enhancers are alkyl chain-containingglycosides derived from maltose and glucose, wherein R₁ contains 8 to 18carbons. The most preferred penetration enhancer is dodecylmaltoside(sometimes referred to herein as "DDM").

The methods and compositions of the present invention are furtherillustrated by the selected embodiments of the invention discussed inthe following examples.

EXAMPLE 1

    ______________________________________                                        Ingredient          Amount (wt. %)                                            ______________________________________                                        Carbopol ® 934  1.0%                                                      Ciprofloxacin HCl   0.35%                                                     Benzalkonium chloride ("BAC")                                                                     0.006%                                                    Dodecylmaltoside ("DDM")                                                                          0.05%                                                     NaOH (1N)           adjust pH to 4.8-5.0                                      ______________________________________                                    

This formulation may be prepared as follows. Starting with 1% Carbopol®solution (pH=3.0), slowly stir and heat the solution to 70°-80° C.(Heating is necessary in order to avoid the formation of an insolubleprecipitate.) Add 0.3% ciprofloxacin into the hot solution and stir veryslowly until all drugs are dissolved. After semi-cool, add 0.006% BACand 0.05% DDM into the solution and stir slowly to avoid air bubbles.Finally, adjust pH to 5.0 with 1N NaOH to form the gel (adding NaOHextremely slowly with pipettes). The percentage of free drugs in gelformulation is 100%. No drug was found to be bound with Carbopol®material.

EXAMPLE 2

Albino rabbits were sacrificed, and within 15 minutes, the corneas weremounted and clamped between two lucite diffusing cells according to thepublished procedure given by Schoenwald. See: Schoenwald, "ComealPenetration Behavior of B-Blocking Agents I: Physiochemical Factors",Journal of Pharmaceutical Science, volume 72, pages 1266-72 (1983). Avolume of 7 ml glutathione bicarbonated Ringer's solution was added tothe endothelial side to serve as the receiver solution. An equal volumeof buffer solution containing drug with or without a penetrationenhancer, lysophosphatidyl-choline ("Lyso PC"), was then added to theepithelial side to serve as the donor solution. The composition of thetwo donor solutions was as follows:

    ______________________________________                                                     Amount (wt. %)                                                   Ingredient     Formulation A                                                                             Formulation B                                      ______________________________________                                        NaCl           0.652       0.652                                              KCl            0.0359      0.0359                                             CaCl.sub.2.2H.sub.2 O                                                                        0.0153      0.0153                                             MgCl.sub.2.6H.sub.2 O                                                                        0.0159      0.0159                                             NaH.sub.2 PO.sub.4                                                                           0.0103      0.0103                                             NaHCO.sub.3    0.2453      0.2453                                             Glucose        0.0903      0.0903                                             Reduced Glutathione                                                                          0.0092      0.0092                                             Ciprofloxacin HCl                                                                            0.03        0.03                                               LysoPC         --          0.01                                               Water          q.s. 100    q.s. 100                                           ______________________________________                                    

The corneal penetration coefficient of drug was determined based on therate of drug appearing in the receiver solution. The results of thisexperiment are presented below:

    ______________________________________                                                 Penetration Coefficient                                                                      Permeation                                                     (cm/sec)       Increase (fold)                                       ______________________________________                                        Formulation A                                                                             2.77 × 10.sup.-6                                            Formulation B                                                                            40.62 × 10.sup.-6                                                                        14.7                                              ______________________________________                                    

The foregoing results clearly indicate that the formulation containing0.01 wt. % lyso PC (i.e., Formulation B) provided a much higher degreeof drug penetration, compared to the control formulation, which did notinclude a penetration enhancer. Based on the foregoing results and otherstudies, it has been concluded that the above-described penetrationenhancers will significantly promote the permeation of any hydrophilicantibiotic whose in vitro corneal penetration coefficient is less than6.0×10⁻⁵ cm/sec.

EXAMPLE 3

New Zealand albino rabbit eyes were selected for evaluation ofciprofloxacin with enhanced sustained vehicle. The followingformulations were tested:

    ______________________________________                                                    Formulation A (solution form)                                     Ingredient  Amount (wt. %)                                                    ______________________________________                                        Ciprofloxacin HCl                                                                         0.35                                                              EDTA        0.05                                                              BAC         0.006                                                             NaAc        0.03                                                              Mannitol    4.6                                                               DDM         0.05                                                              HPMC (E50LV)                                                                              3.3 (viscosity 300 cps)                                           HAc         adjust pH to 4.8-5.0                                              Water       q.s. 100                                                          ______________________________________                                                    Formulation B  Formulation C                                      Ingredient  Amount (wt. %) Amount (wt. %)                                     ______________________________________                                        Carbopol 934                                                                              1.0            1.0                                                Ciprofloxacin HCl                                                                         0.35           0.35                                               BAC         0.006          0.006                                              DDM         --             0.05                                               NaOH (1N)   adjust pH to 4.8-5.0                                                                         adjust pH to 4.8-5.0                               Water       q.s. 100       q.s. 100                                           ______________________________________                                    

The route of administration was topical. The rabbits received 30microliters of either the gel or solution formulations in both eyes. Atthe end of the study, the aqueous humor and cornea were collected andassayed by high performance liquid chromatography to determine the mountof drug present. The results were summarized and are listed in Tables 1and 2 below:

                  TABLE 1                                                         ______________________________________                                        One and Four Hours After Dosing                                                                      Drug Concentration                                             Drug Concentration                                                                           Four Hours                                                     One Hour After Dosing                                                                        After Dosing                                                   (μg/g)      (μg/g)                                              ______________________________________                                        Aqueous humor                                                                 Formulation A                                                                           0.51 ± 0.10   0.21 ± 0.02                                     Formulation B                                                                           0.032 ± 0.020 0.028 ± 0.032                                   Formulation C                                                                           0.69 ± 0.20   0.27 ± 0.06                                     Cornea                                                                        Formulation A                                                                           6.45 ± 1.12   3.19 ± 0.50                                     Formulation B                                                                           1.45 ± 0.34   0.94 ± 0.19                                     Formulation C                                                                           7.90 ± 1.90   3.77 ± 1.75                                     ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Additional Time Points for Enhanced Formulations                                     Drug Concentration (μg/g) Time After Dosing                                                                       24                                     15'  30'    60'    120' 180' 240' 480' hrs                             ______________________________________                                        Agueous                                                                       Humor                                                                         Formulation                                                                            0.06   0.33   0.51 0.52 0.21 0.21 0.077                                                                              0.002                         Formulation                                                                            0.11   0.28   0.69 0.42 0.16 0.27 0.053                                                                              0                             C                                                                             Cornea                                                                        Formulation                                                                            8.25   10.50  6.45 6.18 3.18 3.19 0.96 0.068                         A                                                                             Formulation                                                                            7.60   10.58  7.90 4.28 2.80 3.77 0.63 0.040                         C                                                                             ______________________________________                                    

The foregoing results indicate that in normal eyes, after 30 minutes,drug levels were 10.58 micrograms/gram (ug/g) in cornea, and 0.28 ug/gin aqueous humor. The ciprofloxacin concentration in the aqueous humorreached a maximum of 0.69 ug/g at one hour after topical administrationof 0.3% in a single dose. The results show that the drug has a longerduration time in the cornea for enhanced formulations (i.e.,Formulations A and C). With both enhanced formulations, the drugconcentration in the cornea up to eight hours after administration isstill greater than its MIC90. These ocular tissue concentrations ofciprofloxacin exceeded the MIC 90 of the compound against variousbacteria of ocular pathogens, such as staphylococcus aureus,staphylococcus epidermidis, and pseudomonas aeruginosa. Thus, a singleapplication of the above-described enhanced formulations would besufficient to sterilize the ophthalmic field prior to surgery.

What is claimed is:
 1. A topical ophthalmic composition for sterilizingthe ophthalmic tissues of a human or animal patient in the area ofsurgery prior to an ophthalmic surgical procedure or prophylacticallytreating bacterial infections of the eye resulting from the ophthalmicsurgical procedure, comprising:an antimicrobial effective amount ofciprofloxacin; a carboxy vinyl polymer having a molecular weight of50,000 to 6,000,000; and 0.01 to 1.0 wt. % of dodecylmaltoside.
 2. Amethod of sterilizing the ophthalmic tissues of a human patient in thearea of surgery prior to an ophthalmic surgical procedure, whichcomprises topically applying to the affected eye prior to the surgicalprocedure a single dose of an ophthalmic composition comprising:anantimicrobial effective mount of ciprofloxacin; a carboxy vinyl polymerhaving a molecular weight of 50,000 to 6,000,000; and 0.01 to 1.0 wt. %of dodecylmaltoside.
 3. A method according to claim 2, wherein theophthalmic surgical procedure involves the cornea.
 4. A method ofprophylactically treating ocular bacterial infections resulting from anocular surgical procedure in a human or animal patient, which comprisestopically applying to an eye of the patient which has undergone asurgical procedure a single dose of a composition comprising:anantimicrobial effective amount of ciprofloxacin; a carboxy vinyl polymerhaving a molecular weight of 50,000 to 6,000,000; and 0.01 to 1.0 wt. %of dodecylmaltoside.